RT Journal Article
SR Electronic
T1 In Vitro and in Vivo CYP3A64 Induction and Inhibition Studies in Rhesus Monkeys: A Preclinical Approach for CYP3A-Mediated Drug Interaction Studies
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1546
OP 1555
DO 10.1124/dmd.106.009878
VO 34
IS 9
A1 Prueksaritanont, Thomayant
A1 Kuo, Yuhsin
A1 Tang, Cuyue
A1 Li, Chunze
A1 Qiu, Yue
A1 Lu, Bing
A1 Strong-Basalyga, Kristie
A1 Richards, Karen
A1 Carr, Brian
A1 Lin, Jiunn H.
YR 2006
UL http://dmd.aspetjournals.org/content/34/9/1546.abstract
AB In this study, induction and inhibition of rhesus monkey CYP3A64 versus human CYP3A4 were characterized in vitro, and the corresponding pharmacokinetic consequences were evaluated in rhesus monkeys. In monkey hepatocytes, rifampin markedly induced CYP3A64 mRNA (EC50 = 0.5 μM; Emax = 6-fold) and midazolam (MDZ) 1′-hydroxylase activity (EC50 = 0.2 μM; Emax = 2-fold). Compound A (N-[2(R)-hydroxy-1(S)-indanyl-5-[2(S)-(1,1-dimethylethylaminocarbonyl)-4-[(furo[2,3-b]pyridin-5-yl)-methyl]piperazin-1-yl]-4(S)-hydroxy-2(R)-phenylmethylpentanamide), a known potent and mechanism-based inhibitor of CYP3A4, strongly inhibited the formation of 1′-hydroxy MDZ by recombinant CYP3A64 in a concentration- and time-dependent manner (KI = 0.25 μM; kinact = 0.4 min–1). Similar corresponding results also were obtained with human CYP3A4 in the presence of rifampin or compound A. In rhesus monkeys, MDZ exhibited a relatively high metabolic clearance (primarily via 1′-hydroxylation followed by glucuronidation) and a low hepatic availability (Fh = 16%). Consistent with the induction of hepatic metabolism of a high-clearance compound, pretreatment with rifampin (18 mg/kg p.o. for 5 days) did not significantly affect the i.v. kinetics of MDZ, but caused a pronounced reduction (∼10-fold) in the systemic exposure to MDZ and, consequently, its Fh following intrahepatic portal vein administration (i.pv.) of MDZ. A comparable extent of the pharmacokinetic interaction also was obtained after a 1.8 mg/kg rifampin dose. Also consistent with the in vitro CYP3A64 inhibition finding, compound A (6 mg/kg i.v.) markedly increased (10-fold) the i.pv. administered MDZ exposure. At the doses studied, plasma concentrations of rifampin or compound A reached or exceeded their respective in vitro EC50 or KI values. These findings suggest the potential applicability of the in vitro-in vivo relationship approach in rhesus monkeys for studying CYP3A-mediated interactions in humans. The American Society for Pharmacology and Experimental Therapeutics